Preclinical data presented indicate that psychedelic agents (LSD, psilocybin) have immunomodulatory effects that may promote tumour growth and reduce the therapeutic benefit of immune checkpoint inhibitors, suggesting they could be unsafe during cancer immunotherapy. The authors urge further research to validate these findings amid increasing use of cannabinoids and psychedelics by cancer patients.
The use of Psychedelics by patients with cancer to relieve anxiety and depression has increased in the past few years. Since Psychedelics have immunomodulatory effects, their consumption among cancer patients should be carefully considered due to their potential negative effects on the tumor immune stroma, especially in view of the increase in the utilization of therapeutic approaches that are based on immune activation such as treatment with immune checkpoint inhibitors (ICIs). Preclinical data provided in this report indicate a potentially negative impact on tumor growth as a result of Psychedelics consumption during treatment with ICIs. Furthermore, our research suggests that the use of psychedelic agents (Lysergic acid diethylamide [LSD] or Psylocibin) might diminish the beneficial therapeutic benefits of ICIs. It might be necessary to expend this line of research in order to validate these findings, in view of the increase use of cannabinoids and psychedelics among cancer patients, some of them being treated with immune-based modalities.
Immunomodulation is a key mechanism by which cancers evade host immunity, and immune checkpoint inhibitors (ICIs) such as antibodies targeting PD-1/PD-L1 and CTLA-4 have become important antineoplastic therapies by releasing this inhibition to restore antitumour immune activity. At the same time, cannabinoids and classical psychedelics (serotonergic hallucinogens) are increasingly used by people with cancer for symptom relief, including anxiety, depression, pain, cachexia and inflammation. Earlier preclinical and some clinical work has raised concern that cannabinoids can diminish ICI efficacy, while in vitro studies have suggested that certain psychedelics may exert anti-cancer or anti-inflammatory effects through modulation of innate and adaptive immunity; however, evidence about how psychedelics affect tumour growth in vivo and whether they interact with ICIs during cancer therapy is lacking. Romach and colleagues set out to perform a small-scale preclinical evaluation of two psychedelic agents — lysergic acid diethylamide (LSD) and a psilocybin-containing mushroom extract — using in vitro cytotoxicity assays and an in vivo syngeneic mouse model of E0771 breast cancer, both alone and in combination with an anti-PD-1 antibody. The study aimed to test whether psychedelic exposure influences cancer cell viability and tumour growth, and whether such exposure might interfere with PD-1 inhibitor activity, given possible immunomodulatory effects mediated principally via the serotonin 5-HT2A receptor.
Papers cited by this study that are also in Blossom
Ross, S., Bossis, A. P., Guss, J. et al. · Journal of Psychopharmacology (2016)
Szabo, A. · Frontiers in Immunology (2015)
Szabo, A., Kovacs, A., Frecska, E. et al. · PLOS ONE (2014)
Two complementary experimental approaches were reported: an in vitro cytotoxicity assay using a breast cancer cell line and an in vivo syngeneic mouse model using the E0771 breast cancer model. For the cytotoxicity assay, E0771 cells were plated in 96-well plates and allowed to attach for 16–24 hours at 37°C with 5% CO2. After replacing the medium with assay medium containing test items, cells were exposed to either a psilocybin-containing mushroom extract at 103 µg/ml or LSD at 6.8 µg/ml for 48 hours. Cell viability was assessed using an XTT reagent, with optical density read at 450 nm once vehicle-treated cells reached an OD of 0.5–1.5. The extracted text does not report replicate numbers, controls beyond a vehicle, nor statistical analysis details for the in vitro assay. The in vivo component used a syngeneic E0771 breast cancer model in mice to assess anticancer activity of the same psychedelic preparations, alone and in combination with anti-PD-1 immunotherapy. Test agents were administered orally: the mushroom extract at 0.685 µg per mouse and LSD at 10.3 µg per mouse, five days per week. Anti-PD-1 antibody was given intraperitoneally twice weekly. The extraction does not clearly state mouse strain, sex, group sizes, tumour implantation details, randomisation or blinding procedures, timing of treatment relative to tumour inoculation, or the primary tumour outcome measures (for example, tumour volume endpoints or survival). Figures are referenced in the Results but were not included in the extracted text, and no detailed statistical methods or analysis plan (such as intention-to-treat or specific tests) are reported in the provided sections.
In vitro, both the psilocybin-containing extract and LSD reduced viability of E0771 breast cancer cells in the XTT assay; the text reports that each “induced cell death” in vitro and refers to figures for these data. However, numerical results, percent viability reduction, p-values and replicate numbers are not provided in the extracted material. Contrary to the in vitro cytotoxicity, both psilocybin and LSD were reported to promote tumour growth in the syngeneic E0771 mouse model in vivo; the authors state that these agents “induced tumor growth” and again point to figures for illustration. The extraction does not provide quantitative tumour growth data, statistical comparisons, time courses, or information about whether the tumour-promoting effect occurred when psychedelics were given alone or specifically in combination with anti-PD-1 therapy. Thus, while a qualitative discordance between in vitro cytotoxicity and in vivo tumour-promoting effects is the principal reported finding, the provided text lacks the detailed numerical outcomes, measures of variability and statistical inference needed to fully characterise the effects or their magnitude. Adverse events in animals, effects on immune cell populations, pharmacokinetic data or mechanistic readouts are not reported in the extracted Results section, and the interaction with anti-PD-1 therapy is not explicitly described in terms of outcome measures within the available text.
Romach and colleagues interpret their findings as indicating that psychedelics possess immunomodulatory properties that could be deleterious in the context of cancer immunotherapy. They highlight an apparent discordance: whereas LSD and psilocybin extract showed cytotoxicity against E0771 cells in vitro, both agents were associated with increased tumour growth in the syngeneic mouse model. The authors place these results alongside prior concerns about cannabinoids diminishing ICI activity and suggest that psychedelics might similarly interfere with immune-based cancer treatments. The paper frames psychedelics as generally considered physiologically safe for humans and effective for reducing anxiety and depressive symptoms in people with cancer, but cautions that serotonergic modulation via the 5-HT2A receptor — implicated in cell proliferation and immune regulation — could have unintended effects on tumour immune stroma and on responses to immune activation therapies. The extracted text does not contain a detailed discussion of limitations, but the authors note the preliminary nature of the work and call for expansion and validation of these findings in further studies. They stress the clinical relevance given increasing use of psychedelics among cancer patients and recommend caution when initiating immunotherapy or when considering psychedelic use during cancer treatment, including when ICIs are not being used. No mechanistic data, immune phenotyping, or detailed interaction analyses are presented in the extracted discussion, and the authors do not provide definitive clinical guidance beyond advising prudence and further research to validate and extend these preclinical observations.
The authors conclude that, although psychedelics are used by patients with cancer to alleviate symptoms and treatment-related side effects, their immunomodulatory properties may conflict with cancer treatments, particularly immunotherapy. Given the reported in vivo tumour-promoting signals and the absence of definitive interaction data, Romach and colleagues advise caution regarding psychedelic use in patients who are receiving or planning to receive immunotherapy and call for additional research to validate and clarify these findings.
Immunomodulation is a major pathway used by cancer cells to silence the immune system's natural response and to continue cancer cell proliferation. The field of immunotherapy in general, and checkpoint inhibitors in particular, has progressed significantly during the past several years and is perceived as a new promise for cancer patients. It includes various therapeutic mechanisms that harness the immune system in order to control malignancy. One major class of immunotherapy drugs, that has been approved for clinical use, are antibodies against the Programmed Death receptor 1 (PD1) or its ligand (PD-L1), which directly inhibit the PD1/PD-L1 interaction. Another class of approved immunotherapy is neutralizing antibodies targeting the immune checkpoints T-lymphocyte-associated protein 4 (CTLA-4). In subset of responding patients, this inhibition resulted in activation of the immune system, and as a result diminution of the proliferative process. Psychedelics and Cannabinoids are being used extensively by cancer patient to relieve stress, address cachexia, pain and inflammation. Although not regulatory approved or clinically validated, therapeutic antineoplastic effect has been attributed to cannabinoids, potentially as an auxiliary to chemotherapeutic agents. However, accumulating preclinical and clinical findings clearly demonstrated that their use in patients receiving immune-based therapies (ICIs) should be cautiously considered, in view of increasing evidence that cannabinoids diminish ICIs activity. There is evidence that psychedelic drugs reduce anxiety and depressive symptoms, leading to a decrease in cancer-related demoralization and hopelessness, improved spiritual well-being, and increased quality of life. However, currently, information about their in vivo effect on cancer growth and the potential interaction between Psychedelics and ICIs is lacking. Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Depending on the specific drug, it might affect non-specifically a large spectrum of receptors. However, it is well established, that their main effect is modulated via activation of the serotonin 5-HT2A receptor. 5-HT2A receptor is known to be involved in cell proliferation and it is known that changes in serotonergic innervation may modulate the immune response to inflammatory as well as cancerous processes. Classical psychedelics such as LSD and DMT (N,N-dimethyltryptamine) have been shown, in vitro, to exert anti-cancer and anti-inflammatory effects through the modulation of innate and adaptive immune processes. In view of the increase in their clinical utilization and the concern as potential proproliferative effect modulated via the serotonergic system and their potential immune suppressive activity, we have conducted a small scale evaluation utilizing two psychedelic compound/extracts: Lysergic acid diethylamide (LSD) and "magic mushroom" extract containing Psylocibin in vitro and in vivo utilizing pre-clinical models, with or without PD1 inhibitor, in order to investigate whether there is a merit to the above-mentioned concerns.
Cytotoxicity of a psychoactive plant extract on breast cancer cell line was evaluated . E0771 cells were plated in a 96 well plate, in their culture medium. Cells were allowed to attach for 16-24 hours at 37⁰C and 5% CO2. Thereafter, culture medium was discarded, and fresh assay medium was added to the cells, supplemented with the Test Item (103 µg/ml Psylocibin or 6.8 µg/ml LSD) Cells were incubated for another 48 hours at 37⁰C and 5% CO2. Finally, fresh culture medium was added to the cells along with 50 µL XTT reagent. The Optical Density (OD) was measured using a plate reader once Vehicle treated cells reached the OD range of 0.5-1.5 OD at 450 nm wavelength.
The anticancer activity of psychoactive plant extract and LSD was evaluated in a syngeneic model of E0771 breast cancer in mice, alone or in combination with anti-PD1. Mice were treated PO with a mushroom extract containing Psilocybin (0.685 µg/mouse) and LSD (10.3 µg/mouse) 5 days a week and injected IP with Anti PD1 twice a week.
Both Psilocybin (Fig.) and LSD (Fig.) induced cell death in E0771 breast cancer cell line in vitro. However, Psilocybin and LSD, contrary to the observed in vitro effect, induced tumor growth in a syngeneic model of E0771 breast cancer in mice in vivo (Fig.).
Psychedelics are used by patients with cancer to help relieve cancer symptoms and treatment-related side effects. However, Psychedelics immunomodulatory properties described in this report, suggest Psychedelics could conflict with cancer treatment in general and specifically with immunotherapy. This information can be critical for a large group of patients and requires caution when starting immunotherapy and considering utilization of psychedelic agents even when ICIs are not being used.
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